提升安全性以释放疗效：一类用于实体瘤的新型条件性激活T细胞衔接器

Background: T cell engagers (TCEs) offer potent anti-tumor activity but remain limited in solid tumors by cytokine release and on-target off-tumor toxicity. Amberstone's Tumor-Microenvironment Activated Therapeutics (T-MATE™) platform enables pH-gated activation of TCEs, exploiting tumor acidity to achieve selective activation within tumors while maintaining potency under heterogenous tumor pHs (up to pH 7.2). We previously demonstrated that T-MATE™ TCEs broaden the therapeutic index and enable selective targeting of tumor antigens such as TROP-2, which were previously intractable due to normal tissue expression. Methods: The T-MATE technology integrates proprietary pH-dependent anti-CD3 clones identified via de novo high-throughput functional screening. These clones undergo pH-dependent conformational changes in their CDRs, conferring tunable affinities and selectivity profiles for plug-and-play integration into next-generation TCEs. ABS-106, a STEAP1×CD3 T-MATE TCE, was evaluated for activity against metastatic castration-resistant prostate cancer (mCRPC) using in vitro assays such as cytotoxicity, cytokine release, and repeated-challenge, as well as in vivo xenograft models in humanized mice and non-human primates toxicokinetic studies. Results: ABS-106 demonstrated potent cytotoxicity across tumor-relevant pH ≤7.2 and induced sustained T cell activation and cytokine release comparable to a clinical benchmark TCE. Its pH 7.2 gating minimized activity at physiological pH 7.3-7.5, yielding minimal T cell activation and about 1000-fold lower cytokine release even at high STEAP1 expression. ABS-106 effectively killed STEAP1 Med-Low tumor cells and mediated bystander killing of STEAP1⁻ cells, sustaining activity over nine tumor rechallenge cycles. In vivo , ABS-106 induced dose-dependent tumor regression with increased intratumoral CD8⁺ T cells infiltration and upregulation of pharmacodynamic markers such as Granzyme B, CD69 and PD-1. ABS-106 is fully cross-reactive to cynomolgus CD3 and STEAP1, and exhibited consistent favorable pharmacokinetics (t ₁/₂ 4-5 days) across all animals. Notably, it maintained exposure upon repeat dosing, and was well tolerated at >130× exposure of the benchmark's reported MTD. The molecule demonstrates excellent developability, robust stability under diverse stress conditions, and strong manufacturability characteristics. ABS-106 is currently undergoing IND-enabling studies. Conclusions: ABS-106 exemplifies the precision-engineered, next-gen T-MATE™ TCE with optimal safety-efficacy balance. This smarter, safer TCE design enables potent anti-tumor efficacy while minimizing systemic toxicity, representing a promising therapeutic strategy for solid tumors and other indications.